Formulation of Extended-Release Metformin Hydrochloride Matrix ...

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Tropical Journal of Pharmaceutical Research August 2011; 10 (4): 375-383 © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria.

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Available online at http://www.tjpr.org

http://dx.doi.org/10.4314/tjpr.v10i4.2

Research Article

Formulation of Extended-Release Metformin Hydrochloride Matrix Tablets Basavaraj K Nanjwade*, Sunil R Mhase and FV Manvi

1

KLE University’s College of Pharmacy, Belgaum, Karnataka - 590010, India.

Abstract Purpose: To develop and characterize an oral extended-release matrix tablet of metformin hydrochloride using a combination of a hydrophobic carrier and a hydrophilic polymer, and two types of formulation techniques. Methods: Various metformin hydrochloride formulations containing a hydrophobic carrier (stearic acid) 2 and a hydrophilic polymer (polyethylene oxide) were prepared using a 3 factorial design. Two types of formulation techniques – melt granulation and direct compression – were evaluated. The influence of the carrier, polymer and preparation method on metformin release from the formulations in vitro as well as other physicochemical properties were studied. The release data were subjected to various release kinetic models and also compared with those of a commercial brand. Results: The physicochemical characteristics of all the granules and tablets were generally satisfactory. Optimization results indicate that the release rate of metformin HCl was directly proportional to the levels of stearic acid (SA) and polyethylene oxide (PEO) in the tablet formulations. Release rate was also dependent on the method of granulation used. Kinetic analysis showed that the formulation containing 30 %w/w of polymer exhibited release similar to that of the commercial brand with a similarity factor (f2) of 81.1. Melt granulation was more effective in extending drug release than direct compression. Release 2 mechanism followed most closely the Korsemeyer-Peppas model with a correlation coefficient (r ) and 0.991. Conclusion: The use of a hydrophobic carrier along with a hydrophilic polymer effectively controls the initial rapid release of a highly water soluble drug such as metformin HCl. Hot melt granulation method was especially more effective in achieving this than the direct compression method. Keywords: Metformin hydrochloride, Matrix tablets, Polyethylene oxide, Stearic acid, Hot melt granulation, In vitro release. Received: 23 January 2011

Revised accepted: 22 June 2011

*Corresponding author: E-mail: [email protected]; Tel: +91-8312471399; Fax: +91-8312472387

Trop J Pharm Res, August 2011;10 (4): 375

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INTRODUCTION The major therapeutic goals in subjects with type 2 diabetes are to optimize blood glucose control, reduce overweight, and normalize lipid disturbances and elevated blood pressure. It has been shown that intensive management of type 2 diabetes reduces the risk for chronic complications. However, pharmacological treatment with oral hypoglycemic agents (OHAs) or insulin is often required [1]. Biguanides, in particular, metformin HCI, increase sensitivity to insulin in peripheral tissues of the hosts. It is also involved in inhibition of glucose absorption from the intestine, suppression of hepatic gluconeogenesis and inhibition of fatty acid oxidation [2]. It has an absolute oral bioavailability of 40 to 60 % and gastrointestinal absorption is apparently complete within 6 h of ingestion. An inverse relationship is observed between the dose ingested and relative absorption with therapeutic doses (0.5 to 1.5 g), suggesting the involvement of active, saturable absorption process [3]. Plasma half-life of metformin HCl is 1.5 - 4.9 h [4]. Suitable dosage regimens of the drug include unit doses of 500 mg two to three times daily and can even be built up to five times daily or 850 mg once or twice daily. Such multiple dosing regimens are not preferred since they lead to patient non-compliance, potential side effects and danger of overdosing. There is, therefore, the need to provide formulations and processes that would deliver extended release of metformin HCI from the dosage form when consumed. Furthermore, metformin HCl presents formulation challenges due to its inherently poor compressibility, high dose and high water solubility (> 300 mg/ml at 25 ºC). It belongs to class III of Biopharmaceutical Classification System (BCS) having high water solubility and low permeability [5]. For drugs that are highly water soluble, both

hydrophilic and hydrophobic matrix systems are widely used in oral controlled release drug delivery to obtain a desirable drug release. A direct compression method was reported for the preparation of metformin HCl 500 mg extended-release tablet [6] but on a commercial scale, this may create problems of powder flow down the hopper which would lead to weight variation, as well as poor content uniformity, hardness and friability due to its poor compressibility of metformin HCl. Sustained release microcapsulated preparation of metformin HCl using ethyl cellulose has been reported to give in vitro release up to 22 h; however, preparation of microcapsules on commercial scale as well as optimization are time-consuming and challenging [7]. Several matrix formulations of metformin HCl have been reported based on the use of a hydrophilic (hydroxypropyl methycellulose or carbopol) and/or hydrophobic polymers (e.g., ethylcellulose) but no effort has been made to compare the effectiveness of the production methods. Waxes have been extensively investigated for sustaining the release of drugs. In formulating wax matrix systems, different processing methods, such as dry blending, wet granulation, melt granulation and extrusion spheronization, have been used [89]. Melt granulation method can be used for granulating water sensitive material and producing sustained release granulations. This technique fulfills today’s pharmaceutical industry need because of its simplicity, continuous and efficient process as well as many advantages over conventional methods of granulations such as wet and dry granulation [10,11]. The aim of this work was to prepare matrix tablet containing metformin HCl, as a model water-soluble drug, using a combination of hydrophilic and hydrophobic polymers and evaluate its release characteristics. A secondary objective was to assess the effect


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of granulation method on the release of the drug from matrix tablets.

Preparation of matrix tablets by melt granulation

EXPERIMENTAL

Hot melt granulation technique was used to prepare the drug-wax matrix formulations. First stearic acid was melted in a stainless o steel vessel at 75 C. Metformin HCl was sieved through a 850 µ aperture screen, and heated, spread on a metal tray in an oven at o 75 C. Melt granulation was carried out by transferring the molten metformin HCl to a high shear mixer-granulator (model-Mini RMG, Kevin, India) and then slowly adding the molten stearic acid. Granulation speed was 100 rpm for the impeller and 1500 rpm for the chopper while granulation time was 5 min. The granules were allowed to cool to room temperature by spreading them on metal trays and then sieved through a 850 µ aperture screen.

Metformin HCl powder was a gift from USV Ltd, Mumbai, India while polyethylene oxide (Polyox) was obtained from Colorcon India. Microcrystalline cellulose and magnesium stearate were purchased from Signet Chemicals, India. Other materials used were of analytical grade. Glycomet SR 500 mg tablets (USV Ltd, Mumbai, India), used as the reference metformin sustained release tablets, were purchased from a local pharmacy. Full factorial design Two factors were evaluated, each at three levels, and experimental trials were performed at all possible concentrations. The contents of polyethylene oxide (PEO) and stearic acid (SA) were selected as independent variables. The diffusion exponent (n) and percent drug release at 1 (Q1), 2 (Q2), 4 (Q4), 8 (Q8), 10 (Q10) and 12 h (Q12) were selected as dependent variables. The experimental design used is outlined in Table 1. Table 1: Formulation of Metformin HCl matrix 2 tablet as per 3 factorial design [12-13] Factorial design 3 SA

α1 α2 α3

2

ρ1 M1 M4 M7

PEO ρ2 M2 M5 M8

ρ3 M3 M6 M9

Polyethylene oxide (PEO) concentration: ρ1 = 10 %; ρ2 = 20 %; ρ3 = 30 %; stearic acid (SA) concentration: α1 = 4 %; α2 = 8 %; α3 = 12 %; each formulation contained: metformin HCl – 500 mg, colloidal silicon dioxide – 0.55 %, magnesium stearate – 0.55 %; microcrystalline cellulose - quantity sufficient to 900 mg

The melt granules were mixed with PEO (presieved through a 850 µ screen) and microcrystalline cellulose (pre-sieved through a 600 µ screen), mixed with colloidal silicon dioxide (pre-sieved through a 425 µ screen) and magnesium stearate (pre-sieved through 425 µ screen). The blend was compressed into 19 x 9.7 mm oblong tablets in an 8station Cadmach compression machine. Preparation of matrix tablets by direct compression Batch M6 was selected for this purpose. The drug and microcrystalline cellulose were sieved through a 850 µ screen and manually blended for 5 min. Colloidal silicon dioxide (pre-sieved through a 425 µ screen) was added next and blended for 3 min. Finally magnesium stearate (pre-sieved through a 425 µ screen) was added and mixed for additional 2 min. The final blend was compressed into 19 x 9.7 mm oblong tablets in an 8-station Cadmach compression machine.


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Physicochemical granules

characterization

of

The granules were evaluated for various physicochemical parameters including angle of repose, bulk density, tap density, compressibility index and Hausner ratio. Angle of repose The fixed-funnel method was used to determine angle of repose. The granule formulation was carefully poured through a funnel until the apex of the conical pile just touched the tip of funnel. The height (h) of the pile of the powder and the radius (r) of its conical base were measured and applied to compute the angle of repose (θ) as in Eq 1 [14]. -1

θ = tan h/r …………….……………… (1) Bulk and tap densities A 30 g quantity of the granule samples was placed in a 100 ml dry measuring cylinder and volume, Vo, occupied by it, without tapping, was determined. The cylinder was then given 500 taps using a tap density apparatus (model ETD-1020, Electrolab, India,) and the resulting volume, V500, was noted determined [15-16]. The bulk and tap densities were calculated using Eqs 2 and 3, respectively. Bulk density = W/Vo…………………… (2) Tapped density = W/V500 ………….… (3) where W is the weight of the granules. Compressibility index This parameter was calculated fitting bulk and tap density data (TD and BD, respectively) into Eq 4 [15-16]. Compressibility (C%) = 100 (TD – BD)/TD .… (4)

Hausner ratio This parameter was calculated as the ratio of tap density to bulk density of the granules [15-16].

Physicochemical tablets

characterization

The tablets were evaluated hardness and friability.

for

of

assay,

Determination of drug content Randomly selected tablets (20) from each batch were weighed and powdered. A quantity of the powder, equivalent to 100 mg of metformin HCl, was transferred to a 100 ml volumetric flask and extracted with water. A quantity (1 ml) of filtered solution was diluted to 100 ml with water and the absorbance measured at 233 nm (model UV1201, Shimadzu). Each measurement was carried out in triplicate and the mean taken. Drug concentration was calculated from the calibration curve of a standard (concentration range: 0 to 10 µg/ml). Determination of tablet hardness The hardness of each of 10 tablets randomly selected from each batch was measured with a tablet hardness tester, and the mean and standard deviation evaluation. Determination of tablet friability Tablet friability was assessed using a friabilator (model EF-2, Electrolab, India) at 25 rpm for 4 min. The weight of ten tablets before and after the test, and the percent loss in weight recorded as friability. Evaluation of in-vitro drug release In-vitro drug release assessment was performed using USP type I (basket) apparatus in 900 ml of 0.1M HCl at 37± 5 ºC for the first hour and then with phosphate buffer pH 6.8 for a further 11 h, with the apparatus rotating at 100 rpm throughout the test. Samples were withdrawn at predetermined time intervals and replaced with an equivalent volume of fresh dissolution medium. The withdrawn samples were filtered through a 0.45 µm membrane filter, Trop J Pharm Res, August 2011;10 (4): 378

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suitably diluted and analyzed at 233 nm for metformin HCl by UV-spectrophotometer (Shimadzu UV1201). The content of drug and the cumulative percent drug release were derived from a standard metformin HCL calibration curve. Kinetic analysis of drug release data To analyze the in vitro release data, various kinetic models, including zero order (Eq 5) [17], first order (Eq 6) [18], Higuchi (Eq 7) [19], and Hixson-Crowell cube root law (Eq 8) [20]. C = kot … … … .... … … … … … … .… (5) where, K0 is zero-order rate constant expressed in units of concentration/time and t is the time. Log C = Log C0 kt/2.303 … … … … …… (6)

between 50 and 100 indicate equivalence of two sets of release data [22-23]. n

2

− 0.5

ƒ2 = 50 log { (1 + 1/n∑ t=1 ( R t − T t ) ) × 100 } ………………… ……………. (10)

where Rt and Tt represent the dissolution values of the reference and test products, respectively. Data analysis Statistical evaluation was performed by analysis of variance (ANOVA) using Microsoft Office Excel 2003. The confidence limit was 2 set at 95%. Regression coefficient (R ) was used to determine how well a regression model describes the release data. Mean ± SD for tablet thickness, weight and hardness were calculated by using Microsoft Office Excel 2003.

where, C0 is the initial concentration of the drug and K is first order rate constant. 1/ 2 ….………………………………. (7) Q = Kt

RESULTS

where, K is the constant reflecting the design variables of the system. 1/3 1/3 Q0 – Qt = KHC t … … ……………….. (8)

Table 2 summarizes the physicochemical properties (bulk density, tapped density, angle of repose, Carr’s index and Hausner ratio) of the granules.

Similarity factor (ƒ2), computed as in Eq 10, was used to compare differences in drug release profile. Similarity factor (ƒ2) values

Carr’s index (%)

Hausner ratio

Assessment of similarity factor

Angle of repose (o)

where Mt/M∞ is the fraction of drug released at time t, K is the rate constant and n is the release exponent. The n value was used to characterize different release mechanisms for cylindrical shaped matrices.

Tapped density (g/ml)

A simple relationship, Korsmeyer–Peppas model [21], was applied to determine the mechanism of drug release as in Eq 9. n Mt/M∞= Kt ……………………………… (9)

Bulk density (g/ml)

Mechanism of drug release

Table 2: Physicochemical properties of metformin granules Formulation Code

where, Qt is the amount of drug released in time t, Q0 is the initial amount of the drug in tablet and KHC is the rate constant for HixsonCrowell rate equation.

Evaluation of granules

M1 M2 M3 M4 M5 M6 M7 M8 M9 DC

0.53 0.56 0.61 0.54 0.57 0.63 0.55 0.59 0.65 0.51

0.66 0.69 0.74 0.67 0.7 0.76 0.67 0.73 0.78 0.64

39.8 36.6 38.0 38.1 37.3 35.8 37.2 37.5 35.6 41.2

19.7 18.8 17.6 19.4 18.6 17.1 17.9 19.2 16.7 20.3

1.25 1.23 1.21 1.24 1.23 1.21 1.22 1.24 1.20 1.25

The bulk density of the granules ranged from 0.51 - 0.65 gm/ml and tapped density from 0.64 - 0.78 g/ml. The angle of repose of the granules prepared by melt granulation Trop J Pharm Res, August 2011;10 (4): 379

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method was in the range 35.6 - 39.8º while it was 41.2º for the direct compression granules. The compressibility (Carr’s index) for all the formulations was < 25 % while Hausner ratio was in the range 1.20 -1.25.

in Figs 1 and 2. Over the period of 12 h, the drug release rate for M1 and M9 formulations decreased as the concentration of polyethylene oxide increased. 120

characteristics

(a )

of

Table 3 indicates the results of the various physicochemical tests (hardness, friability and assay) performed on the tablet formulations. Table 3: Physicochemical evaluation of metformin HCl tablets Formulation code

Hardness (N)a, n=10

Friability (%), n=10

Assay (%) n=20

M1 M2 M3 M4 M5

80 ± 4 78 ± 4 74 ± 4 75 ±2.83 74 ± 3.95

0.21 0.25 0.31 0.28 0.26

99.92 99.96 100.10 100.02 99.97

M6 M7 M8 M9 DC

76 ± 2.07 79 ± 2.62 75 ± 4.14 70 ± 4.58 66 ± 5.74 a Mean ± SD

0.19 0.21 0.23 0.28 0.42

99.95 98.20 99.20 97.85 99.58

The hardness of the tablets produced by melt granulation (formulation M1 – M9) and direct compression (formulation DC) was in the range 70 - 80 N for the former and 66 N for the latter. All the formulations showed less than 1 % friability which is within the prescribed limit. Drug content was uniform within each batch and ranged from 97.85 – 100.10 % of the theoretical value. Evaluation of in-vitro release The in-vitro drug release results for the test and reference (commercial brand) tablets are shown in Figs 1 and 2. The release results for the formulations composed of polyethylene oxide (PEO) in the range of 10, 20, 30 % w/w and stearic acid (SA) in the range of 4, 8, 12% w/w are shown

C u m % R e le a s e

100 80 60 40 20 0 0

1

2

4

6

8

10

12

8

10

12

T im e ( h )

120

(b )

100 80 C u m % R e le a s e

Physicochemical metformin tablets

60 40 20 0 0

1

2

4 6 T im e ( h )

Fig 1: Comparative release profiles of metformin HCl tablets with varying PEO content (a): M1= X; M2 = ■; M3 = ▲; and (b) M4= X; M5 = ■; M6 = ▲; DC = ж; reference (commercial) product = o

The release profile of M6 formulation (which contains 30 %w/w of PEO and 8% w/w of SA) is similar to that of the reference (commercial) product based on the similarity factor (f2) value of 81.08. Kinetic analysis of the release data indicates that formulation M6 fitted best to both Higuchi and KorsemeyerPeppas models with correlation coefficients of 0.9780 and 0.9910, respectively, and n value of 0.4967.


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120

(a )

100


80 60 40 20 0 0

1

2

120

4 6 T im e ( h )

8

10

12

(b )

100


80

granule formulations, M9 (the optimized formulation) had the largest granules, as well as the highest bulk and tapped densities (Table 2). M9 granules were probably more regular in shape, producing a more uniform distribution, with smaller void spaces between the particles. Carr’s index (CI) is usually indicative of the flowability and degree of packing of the material; these are important parameters when filling a matrix formulation into the die of the tablet press. A CI of < 15 % indicates adequate granule flow and stable packing, while values > 25 % are characteristic of poor flow properties. The Hausner ratio is usually related to the compressibility of powder and values < 1.25 are indicative of good compressibility. All the formulations had CI < 25 % and Hausner ratio ≤ 1.25 indicating good to passable flow irrespective of the method of granulation. The drug content of all the formulations ranged from 98.2 -100.1 %, indicating the presence of an acceptable amount of drug in the formulations. Furthermore, all the formulations showed satisfactory hardness and friability.

60 40 20 0 0

1

2

4 6 T im e ( h )

8

10

12

Fig 2: Comparative release profiles of metformin HCl with (a) varying PEO content: M7 = X; M8 = ■; M9 =▲; reference (commercial) product = o; and with (b) varying SA content: M3 = X; M6 = ■; M9 =▲

DISCUSSION A suitable extended release metformin HCl dosage form would not only enhance therapeutic efficacy and patient compliance but also produce more desirable blood drug levels and lower incidence of adverse effects. The density of a material depends on the shape and size of the particles. The density is normally proportional to the number of spherical particles present in the bulk, and inversely proportional to the size of particles [24]. Notwithstanding this, out of all the nine

The decrease in drug release rate as the concentration of polyethylene oxide increase is consistent with the findings of Rajkumar at el [25], which indicate that the presence of a highly water soluble compound in polyethylene oxide matrix results in a faster rate of polymer swelling and a large increase in gel thickness to prevent immediate tablet disintegration, and thus controlling the diffusion of the drug. Increase in polymer concentration not only caused increase in the viscosity of the gel but also led to a decrease in the diffusion of drug and, therefore, a reduction in the drug release rate [26]. Other factors at play in relation to polymer content probably include change in water penetration rate, water absorption capacity and polymer swelling [27]. Also, the decrease in drug release rate when the stearic acid content of the matrix was increased may be due to slower penetration Trop J Pharm Res, August 2011;10 (4): 381

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of the dissolution medium in matrices as a result of increased lipophilicity [28] while the initial burst release from the matrix can probably be attributed to the dissolution of drug from the tablet surface. Further, penetration of dissolution fluid was hindered by the hydrophobic coating of stearic acid around the drug particles, leading to diminished drug release over an extended period [29].

ACKNOWLEDGEMENT The authors are thankful to USV Ltd. Mumbai, India and Colorcon India for providing, free of charge, the drug and polyethylene oxide, respectively, used in the study.

REFERENCES 1.

The slower drug release from the tablets derived by melt granulation (compared with those prepared by direct compression) could be due to the formation of a more uniform, and hence, a more effective and rigid hydrophobic coating of stearic acid around the hydrophilic drug particles during hot melt granulation. An ideal matrix formulation should contain polymers and diluents at amounts as little as possible, and release its drug content in a sustained release profile over a reasonable length of time, preferably by zero-order kinetics [30]. On fitting M6 data into various release models, the highest regression coefficients, 0.9780 and 0.9910, were for Higuchi and Korsemeyer-Peppas models, respectively, with n value of 0.4967 which indicates a coupling of diffusion and erosion mechanism, so-called anomalous diffusion. This iindicates, therefore, that drug release from the tablets was controlled more by polymer swelling, followed by drug diffusion through the swollen polymer, and then slow erosion of the tablet matrix.

CONCLUSION An extended release tablet formulation of metformin HCl was successfully developed using a combination of hydrophobic and hydrophilic polymers. The matrix tablet formulation demonstrated the desired drug release profile. Melt granulation is more effective than direct compression for controlling the release of a highly water soluble drug such as metformin HCl.

Reinhard GB, Medding JU, Sabine A, Thomas L. A direct efficacy and safety comparison of insulin aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes. Diabetes Care 2004; 27(3): 10231027. 2. Diabetes Information, [cited 2010 Oct 13]. Available from: www.diabetesnet.com/diabetes_treatments/me tformin.php 3. Antarkar AK, Lala RG, Kamdar NM. Multilayer tablets containing thiazolidinedione and biguanides and methods for producing them [cited 2010 Oct 13]. Available from: http://www.freepatentsonline.com/y2006/0057 202.html 4. Bailey CJ, Turner RC. Metformin. New Engl J Med 1996; 334(9): 574-579. 5. Nicklin P, Keates AC, Page T, Bailey CJ. Transfer of metformin across monolayers of human intestinal Caco-2 cells and across rat intestine. Int J Pharm 1996; 128: 155-162. 6. Fiona P, Marina L, Ali RS. Investigation of a directly compressible metformin HCl 500 mg extended release formulation based on hypromellose, Poster reprint, Controlled Release Society Annual Meeting, 2005 [Cited 2010 Oct 13]. Available from: www.colorcon.com. 7. Guhan B, Peter T, Douglas SG, Punit HM. In vitro– in vivo correlation (IVIVC) models for metformin after administration of modified release (MR) oral dosage forms to healthy human volunteers. 2001; 90(8): 1176-1185. 8. Passerini N, Apertini B. Preparation and characterization of ibuprofen-poloxamer 188 granules obtained by melt granulation. Eur J Pharm Sci 2002; 15: 71-78. 9. Saraiya D, Bolton S. The use of precirol to prepare sustained release tablet of theophylline and quinidine gluconate. Drug Dev Ind Pharm 1990; 16: 1963-1969. 10. Taggart CM, Ganley JA, Sickmuller A, Walker SE. The evaluation of formulation and processing conditions of melt granulation process. Int J Pharm 1984; 19: 139-48. 11. Royce A, Suryvansh J, Shah U and Vishupad K. Alternative granulation technique: Melt granulation. Drug Dev Ind Pharm 1996; 22: 917-924.


Nanjwade et al 12. Shoufeng LJ, Senshang LB, Bruce P, Haresh L. Effect of HPMC and Carbopol on the release and floating properties of Gastic Folating Drug Delivery System using factorial design. Int J Pharm 2003; 253: 13-22. 13. Dasharath MP, Natavarlal MP, Viral FP, Darshini AB. Floating granules of ranitidone Hydrochloride Gelucire 43/01: Formulation optimization using factorial design. AAPS Pharm Sci Tech 2007; 8(2): E1-E7. 14. Streubel A, Siepmann J, Bodmeier R. Floating matrix tablets based on low density foam powder: effects of formulation and processing parameters on drug release. Eur J Pharm Sci. 2003; 18: 37-45. 15. Ohwoavorhua FO, Adelakun TA. Some physical characteristics of microcrystalline cellulose obtained from raw cotton of cochlospermum planchonii. Trop J Pharm Res 2005; 4(2): 501507. 16. Murtaza G, Ahmed M, Shahnaz G. Microencapsulation of diclofenac sodium by non-solvent addition technique. Trop J Pharm Res 2010; 9(2): 187-195. 17. Hadjiioannou TP, Christian GD, Koupparis MA, Macheras PE. Quantitative Calculations in Pharmaceutical Practice and Research, VCH Publishers Inc, New York: 1993; p 345-348. 18. Bourne DWA. Pharmacokinetics. In: Banker GS, Rhodes CT, editors. Modern Pharmaceutics. 4th ed. Marcel Dekker Inc, New York: 2002; pp 67-92. 19. Higuchi T. Mechanism of sustained action medication, Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 1963; 52: 1145-1149. 20. Hixson AW, Crowell JH. Dependence of reaction velocity upon surface and agitation (I) theoretical consideration. Ind Eng Chem 1931; 23: 923-931. 21. Korsmeyer RW, Gumy R, Doelker E, Buri P, Peppas NA. Mechanism of solute release from porous hydrophilic polymer. Int J Pharm 1983; 15: 25-35.

22. Shujaat AK, Mahmood A, Ghulam M, Muhammad NA, Nisar UR, Rozina K, Fatima R, Mohammad A. Formulation of nimesulide floating microparticles using low viscosity hydroxypropyl mehylcellulose. Trop J Pharm Res 2010; 9(3): 293-299. 23. Moore JW, Flanner HH, Mathematical comparision of dissolution profiles. Pharm. Technol.1996; 20: 64-74. 24. Banker GS, Anderson NR. Tablets. In: Lachman L, Lieberman HA, Kanig JL., editors. The theory and practice of industrial pharmacy. 3rd ed. Philadelphia: Lea and Febiger; 1987; pp 293345. 25. Rajlumar M, Kiran JP, Vidyasagar CH, Venkateswara RB, Kirankumar A, Nagarjuna I, Srinivasa RP, Ravikiran J. Formulation and evaluation of controlled release matrix tablets of trimtazidine dihydrochloride. J Chem Pharm Res 2010; 2(3): 746-753. 26. Lisa MA. Use of domperidone as a prokinetic and antiemetic, health and wellness. Int J Pharm 2005; 9: 120-125. 27. Wan LSC, Heng PWS, Wong LF. Releationship between swelling and drug release in hydrophilic matrix. Drug Dev. Ind. Pharm 1993; 19: 1201-1210. 28. Hamdani J, MoesAJ, Amighi K. Development and evaluation of prolonged release pellets obtained by the melt pelletization process. Int J Pharm 2002; 245:167-177. 29. Yonezava Y, Ishida S, Sunanda S. Release from or through a wax matrix system:I, basic release properties of the wax matrix system. Chem Pharm Bull 2001; 49:1448-1451. 30. Apurba SA, Atiqul HP, Dilasha S, Golam K, Reza-ul J. Investigation of in vitro release kinetics of carbamazepine from Eudragit RSPO and RLPO matrix tablets. Trop J Pharm Res 2009; 8(2): 145-152.
